PROJECT SUMMARY/ABSTRACT The Philadelphia chromosome?positive (Ph+) leukemias, including chronic myeloid leukemia (CML) and Ph+ B- cell acute lymphoblastic leukemia (B-ALL), are prevalent blood cancers for which our current therapies are inadequate. While BCR-ABL1 tyrosine kinase inhibitors (TKIs) such as imatinib mesylate have replaced hematopoietic stem cell transplantation (HSCT) as initial therapy for CML, complete molecular remissions are rare and acquired resistance to TKI therapy is a significant clinical problem. Eligible Ph+ B-ALL patients undergo allogeneic HSCT in first remission following chemotherapy, but over half will relapse. Hence, it is likely that current therapy will not cure most Ph+ leukemia patients, and effective methods to eradicate residual leukemia are needed. To accomplish these goals, well-characterized mouse models of CML and B-ALL will be utilized to investigate several highly relevant questions about the biology and pathogenesis of these leukemias that are difficult to address using cell lines or primary human leukemia samples. In the first Aim, a binary conditional transgenic mouse model of CML will be used to investigate the mechanism of primary resistance to TKI therapy and determine if interventions that increase leukemia stem cell cycling increase the rate of molecular remission. To extend adoptive cellular immunotherapy to myeloid leukemia, a chimeric antigen receptor directed against a CML stem cell antigen will be developed and tested. In the second Aim, a novel hypothesis that mutations in the transcription factor IKAROS underlie the biology of a major subset of high-risk (Ph+ and Ph-like) B-ALL will be tested, and the mechanism of resistance of IKAROS-mutant B-ALL to therapy determined. Together, these studies should yield important new knowledge that will improve the effectiveness of our current treatments for Ph+ leukemia, and increase the proportion of patients that are cured of their disease.